Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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TRANSDERMAL SYSTEMS HAVING CONTROL DELIVERY SYSTEM
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S. published
application US2006/0188558, filed February 18, 2005, entitled
Transdermal Systems Having Control Delivery System.
FIELD OF THE INVENTION
[0002] The present invention relates to transdermal delivery systems.
More particularly, the present invention relates to transdermal
delivery systems for delivering active agents to the skin or mucosa of
a patient. Still more particularly, the present invention relates to
such transdermal delivery systems in which a polymer membrane is
utilized for controlling the rate of transmission of the active agent
there through.
BACKGROUND OF THE INVENTION
[0003] A considerable number of drug delivery devices are known in the
art. These devices generally provide for a drug or other active agent
to be released by diffusion from a reservoir or the like through the
surface of the device to the skin or mucosa of a patient for the drug
or other active agent. Most of the current transdermal systems can be
divided into two major classes; that is, either reservoir systems or
matrix-type systems. The reservoir systems generally comprise an
enclosure of some kind filled with a fluid preparation of the active
ingredient. In these systems, one side of the enclosure consists of a
membrane which is permeable at least with respect to the active
ingredient, and which is normally provided with a suitable adhesive. In
the latter or matrix-type systems, the active ingredient is generally
incorporated into a gel-type formulation or adhesive matrix, which is
preferably also self-adhesive.
[0004] In connection with various membrane-containing devices, one
objective has been to control the rate of administration, such as to
delay the onset of therapeutic effect for significant time
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periods after application of the device. One such device, for
example, is disclosed in Lee et al., U.S. Patent No. 5,284,660.
Like the others, this device employs one or more membranes between
the agent reservoir and the surface where the agent is to be
released. The membrane in this case is substantially free of
undissolved agent, and is preferably formed from a material having
low permeability in a first state and high permeability in a second
state. The membranes are described as comprising various polymers
which are hydrophilic or semi-hydrophilic, including polyvinyl
alcohol, polyvinyl pyrrolidone, hydroxypropylcellulose,
hydroxyethylcellulose, and hydroxypropylmethylcellulose.
[0005] In another prior art reference, Becher, U.S. Patent
No. 5,066,494, a multi-chamber system is used in order to attempt
to obtain better control over transdermal drug application. Such a
system is also said to help in preventing the flowing or dropping
out of the complete active substance formulation therefrom.
[0006] In many devices, there is also a desire for an initial
rapid drug administration or spike, and in the past this has been
obtained, for example, by employing a contact adhesive layer in
which the drug is contained. In references such as Reed, U.S.
Patent No. 4,877,618, a relatively constant but declining rate of
administration is said to be obtained over extended time periods by
employing a number of particulate-containing interlaminar layers
which absorb the drug.
[0007] Another device is shown in Becher et al., U.S. Patent
No. 5,902,433, which in this case includes a number of chambers
containing active substance, the chambers being in communication
with each other, which are formed from top and bottom layers with
an active-agent-containing substance therebetween, in which the top
and bottom layers are brought together at predetermined sites to
form channels or chambers thereof.
[0008] Another multi-compartment device is shown in Andriola
et al., U.S. Patent No. 4,666,441. In this case, the reservoir
area is formed from a permeable porous membrane which is meant to
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control the rate of drug movement, and the membranes include
polycarbonates, polyvinyl chlorides, polyamides, polysulf ones, and
the like.
[0009] Yet another patent disclosing a patch employing a
membrane is Cavazza, U.S. Patent No. 5,683,712. In this case, a
microporous membrane is used to control the drug release through a
subsequent adhesive layer and gel layers containing the drugs in
question. No specific membrane materials are disclosed for this
purpose in this patent.
[0010] Yet another transdermal product for application of active
agents is disclosed in Kwiatek et al., U.S. Patent No. 5,503,844.
This patent discloses the use of cellular foam layers for use as
carrier layers for active agents, with or without additional
membrane layers. The foam layers disclosed in this patent are
polyurethane foams, and conventional rate-controlling polymers are
used therein.
[0011] A transdermal system which has already been marketed is
the ESTRADERM system marketed by Novartis, as shown schematically
in Fig. 1 hereof. This system includes a patch product which
includes an outer transparent polyester film 3, a drug reservoir 4
of estradiol and alcohol gelled with hydroxypropylcellulose, an
ethylene vinyl acetate copolymer membrane 6, and an adhesive
formulation 8 of light mineral oil and polyisobutylene. This is
covered by a protective liner 10 of siliconized polyethylene
terephthalate film for removal prior to use. The alcohol acts as a
solvent or enhancing agent for movement of the drug through the
skin. However, when the alcohol has been depleted, no driving
force for the drug remains. As in the cases discussed above, the
membrane utilized in this product is not only non-microporous, but
does not have a capacity to retain a fluid composition, or an
enhancing agent, therein.
[0012] There has thus developed a strong need for an improved
patch system, and in particular one in which a membrane is employed
which has a capacity to retain solvent and/or enhancing agents,
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such as volatile organic solvents, therein for the purpose of
improving and controlling the delivery of the drug itself and
improving the solubility of the drug in the patch systems utilized.
[0013] It is also true that in many of the present transdermal
systems, since the systems including adhesive compositions must be
subjected to rigorous drying conditions prior to use, that the drug
itself also needs to be subjected to these conditions. Thus,
systems have also been designed in which it does not prove
necessary to subject the drug to such conditions and thereby
improve its stability.
[0014] In many of the present systems, it is necessary that if a
solvent is employed, it must at least be partially miscible with
the adhesive systems utilized. Therefore, systems have also been
sought in which one can employ solvents that are not fully
compatible with the adhesive blend therein.
[0015] It is also apparent that in most of the prior transdermal
systems the amount of solvent which can be retained in the patch
itself is limited to the saturation concentration of the solvent in
the adhesive itself. Therefore, systems have been sought which are
not limited by this factor.
SUMMARY OF THE INVENTION
[0016] In accordance with the present invention, these and other
objects have now been realized by the discovery of a transdermal
delivery system for delivering an active agent to the skin or
mucosa of a patient comprising a backing layer, a polymer membrane
disposed within the backing layer, an adhesive layer for attaching
the transdermal delivery system to the skin or mucosa of the
patient, and a releasable layer for covering the adhesive layer
prior to attachment of the transdermal delivery system to the skin
or mucosa of the patient, the polymer membrane impregnated with a
predetermined amount of a fluid medium for altering the rate of
transmission of the active agent through the skin or mucosa of the
patient, the predetermined amount of the fluid medium being
substantially greater than the amount of that fluid medium retained
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by the polymer membrane upon drying of the polymer membrane.
Preferably, the fluid medium comprises a liquid solvent for the
active agent, or an enhancer for the active agent, or an excipient
(or solution of an excipient) for the active agent, or the active
agent itself.
[0017] In accordance with another embodiment of the transdermal
delivery system of the present invention, the adhesive layer
comprises a first adhesive layer, and the device includes a second
adhesive layer disposed between the backing layer and the polymer
membrane.
[00181 In accordance with another embodiment of the transdermal
delivery system of the present invention, the first and second
adhesive layers comprise an adhesive matrix including one or more
adhesives such as an acrylic, silicone, polyisoalkaline, rubber,
vinyl acetate, polyisobutylene rubber, polybutadiene,
styrene-butadiene, cellulose derivatives, polysaccharides,
polyurethane elastomers, and polyester elastomers.
[0019] In accordance with another embodiment of the transdermal
delivery system of the present invention, the fluid medium
comprises a solvent for the active agent. In a preferred
embodiment, the solvent comprises a C2-C8 alcohol.
[0020] In accordance with another embodiment of the transdermal
delivery system of the present invention, the first adhesive layer
includes the active agent. In another embodiment, the second
adhesive layer includes the active agent. Preferably, both the
first and second adhesive layers include the active agent.
[0021] In accordance with another embodiment of the transdermal
delivery system of the present invention, the polymer membrane
comprises a hydrophilic or hydrophobic polymer(s) or copolymer. In
a preferred embodiment, the hydrophilic or hydrophobic polymer(s)
or copolymer are selected from the following: polyolef in (e.g.,
polyethylene, polypropylene), ethylene vinyl acetate, polyvinyl
acetate, polyether block amides, polyurethane, polyamides (e.g.,
nylon), cellulose and cellulose derivatives, polyvinyl chloride,
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polyvinyl alcohol, polystyrene, polymethyl methacrylate,
polysilane, and polysiloxane.
[0022] In accordance with yet another embodiment of the
transdermal delivery system of the present invention, the
predetermined amount of the fluid medium comprises from about 0.5
to 10 mg/cm2. In the preferred embodiment, the predetermined amount
of the fluid medium comprises from about 1 to 7 mg/cm2. Most
preferably, the predetermined amount of the fluid medium comprises
about 3.0 mg/cm2.
[0023] In accordance with another embodiment of the transdermal
delivery system of the present invention, the first and second
adhesive layers comprise adhesives which are at least partially
resistant to plasticization by a solvent for the active agent.
[0024] In accordance with one embodiment of the transdermal
delivery system of the present invention, the system comprises a
backing layer, a polymer membrane disposed within the backing
layer, an adhesive layer for attaching the transdermal delivery
system to the skin or mucosa of the patient, a releasable layer for
covering the adhesive layer prior to attachment of the transdermal
delivery system to the skin or mucosa of the patient, and a fluid
medium distributed between the adhesive layer and the polymer
membrane in a manner such that between about 2.5% and 100% of the
fluid medium is disposed in the polymer membrane. Preferably,
between about 50% and 100% of the fluid medium is disposed in the
polymer membrane. In one embodiment, a greater proportion of the
fluid medium is disposed in the polymer membrane than is disposed
in the adhesive layer.
[0025] In accordance with the present invention, a method has
also been discovered for manufacturing a transdermal delivery
system for delivering an active agent to a patient in which the
method comprises preparing an adhesive layer for attaching the
transdermal delivery system to the skin or mucosa of the patient,
providing a polymer membrane, impregnating the polymer membrane
with a predetermined amount of a fluid medium for altering the rate
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of transmission of the active agent through the skin or mucosa of
the patient, drying the adhesive layer without drying the polymer
membrane, applying the adhesive layer to the impregnated polymer
membrane, providing a backing layer and incorporating the adhesive
layer and the polymer membrane into the backing layer, and
providing a releasable liner adjacent to and protecting the
adhesive layer prior to application of the transdermal delivery
system to the skin or mucosa of the patient. In a preferred
embodiment, the fluid medium comprises a solvent for the active
agent, or an enhancer for the active agent, or an excipient (or
solution of excipient) for the active agent, or the active agent
itself.
[0026] In accordance with one embodiment of the method of the
present invention, the adhesive layer comprises a first adhesive
layer, and the method includes applying a second adhesive layer
between the backing layer and the polymer membrane. In a preferred
embodiment, the first and second adhesive layers comprise an
adhesive matrix including an adhesive such as one of the following:
acrylic, silicone, polyisoalkaline, rubber, vinyl acetate,
polyisobutylene rubber, polybutadiene, styrene-butadiene, cellulose
derivatives, polysaccharides, polyurethane elastomers and polyester
elastomers.
[0027] In accordance with one embodiment of the method of the
present invention, the fluid membrane comprises a solvent for the
active agent. In a preferred embodiment, the solvent for the
active agent comprises a C2-C18 alcohol.
[0028] In accordance with another embodiment of the method of
the present invention, the method includes adding the active agent
to the first adhesive layer. In another embodiment, the method
includes adding the active agent to the second adhesive layer. In
a preferred embodiment, the method includes adding the active agent
to both the first and second adhesive layers.
[0029] In accordance with another embodiment of the method of
the present invention, the polymer membrane comprises a polymer
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such as either a hydrophilic or hydrophobic polymer. Preferably,
the hydrophilic polymer is a polyolef in (e.g., polyethylene) or
polyethylene/ethylene vinyl acetate copolymer.
[0030] In accordance with another embodiment of the method of
the present invention, the predetermined amount of the fluid medium
comprises from 0.5 to 10 mg/cm2, preferably from about 1 to
7 mg/cm2, and most preferably 3.0 mg/cm2.
[0031] In accordance with another embodiment of the method of the
present invention, the first and second adhesive layers comprise
adhesives which are at least partially resistant to plasticization
by the solvent for the active agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] The present invention may be more fully understood with
reference to the following detailed description which, in turn,
refers to the figures, in which:
[0033] FIG. 1 is a side, elevational, enlarged, cross-sectional
view of a liquid reservoir transdermal device in accordance with
the prior art; and
[00341 FIG. 2 is a side, elevational, enlarged, cross-sectional
view of a transdermal device in accordance with the present
invention;
DETAILED DESCRIPTION
[0035] Referring first to FIG. 1, a transdermal patch product of
the prior art is shown therein. The prior art product is intended
to represent known products, such as the ESTRADERM transdermal
patch product sold by Novartis. This patch product includes a
backing layer 2 which is impermeable to fluids contained within the
patch, and a reservoir 4 comprising a drug or active agent along
with an alcohol-containing fluid gel reservoir composition. A
conventional microporous membrane 6 is then included along with an
adhesive layer also containing active agent or drug therein. The
patch is covered by a releasable liner 10 which is removed prior to
application of the adhesive layer 8 to the skin or mucosa of the
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patient. Use of alcohol-like substances acts as an enhancer since these
small molecule compositions can travel through the skin far faster than
the drug components used in these products . The alcohol material thus
initially carries additional amount of the drug (estradiol in this
case) through the skin, and the patient receives an initial "spike" of
drug composition. However, as soon as the alcohol is depleted, little
driving force remains for the estradiol to pass through the skin of the
patient. Attempts have thus been made to obtain equivalent "spikes" of
the drug composition without using materials such as alcohol. These
attempts have not proven to be successful, however.
[0036] Referring to PIG. 2, a comparable transdermal patch product of
the present invention is shown, including backing layer 12; first
adhesive layer 14, preferably containing active agent therein; membrane
16; a second adhesive layer 18, again preferably containing active
agent therein; and releasable liner 20 thereon.
[0037] In a preferred composition as shown in FIG. 2, in addition to
the polymer membrane 16, either one of adhesive layers 14 or 18, or
both, are preferably employed. Furthermore, even when two adhesive
layers 14 and 18 are used, they can constitute different adhesive
formulations, and one or the other or both of these adhesive layers 14
and 18 can include the active agent itself dispersed therein. As a
separate matter, the polymer membrane 16 can include active agent
dissolved in the solvent contained within the pores of the membrane.
This, of course, can also be the only source of active agent, or active
agent can in addition be included in one or both of adhesive layers 14
and 18. These various combinations permit one to custom make the
specific transdermal patch system so that an appropriate drug and drug
application regimen can be provided. This can include an initial
"spike" in the drug delivery, it can include a shortening of the lag
time between application of the patch and drug delivery, and it
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can alter the solubility of the drug in the system or constituent
layers for such purposes.
[0038] The polymer membrane 16 is an essential element of the
present invention, since it must have sufficient capacity (via
pores or as a result of swelling) so as to retain solvent or other
fluid media within the membrane. Thus, the presence of such
volatile organic solvents in the membrane of the present invention
helps improve the delivery of the drug by acting as an enhancer
and/or by improving the solubility of the drug in the patch itself.
Thus, while volatile solvents were used in the past, much of the
solvents were driven off during drying of the patches prior to use.
In accordance with this invention, however, it is possible to
thoroughly dry the adhesive matrix without driving off the solvent
which is desired, by incorporating the solvent into the membrane in
accordance with this invention, preferably subsequent to the drying
process.
[0039] There are thus at least two elements which combine to
provide the present invention. First, there is the incorporation
of a fluid medium into the membrane itself. Second, there is the
drying of the adhesive layer or layers, or indeed all of the patch
except for the membrane, prior to completion of the patch; i.e.,
separately from the membrane. Thus, the membrane itself is not
subjected to the drying conditions; i.e., elevated temperatures,
which are applied to the adhesive layer (s) themselves. It is in
this manner that it now becomes possible to incorporate into these
transdermal systems far greater amounts of these fluid media than
has previously been the case.
[0040] The advantages now achievable by means of this invention
include the ability to more accurately control the overall drug
application process, such as by applying or extending the period of
a drug "spike" and/or the entire period of drug application. It is
also now possible to utilize larger amounts of fluid media which
would normally result in reduction, or even elimination, of the
adhesive character of the adhesive layer(s) if applied thereto. In
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addition, it is also possible to utilize a fluid medium which is
entirely incompatible with the adhesive layer(s), since the fluid
does not need to be carried by that adhesive layer(s), but can be
retained by the polymer membrane. All of this permits a radical
alteration in the overall design of these transdermal drug delivery
systems.
(0041] There are many transdermal systems which are known to
employ membranes, primarily for rate-controlling purposes, or as a
component in a gel reservoir system such as that set forth above.
However, the membranes of the present invention, employed in the
specific systems hereof, perform an entirely different function;
namely, of retaining solvent, enhancer, excipient and/or drug
compositions for the purpose of controlling the application of the
drug, modifying the rate of drug delivery, or selectively modifying
the solubility of the drug in the system.
[0042] The membranes usable in accordance with the present
invention possess sufficient capacity to retain within the membrane
greater than 5 mg/10 cm2 of solvents such as short chain alcohols (2
to 18 carbon atoms, preferably ethyl alcohol) preferably from 5 to
100 mg/10 cm2, and preferably at least about 30 mg/10 cm2.
[0043] The polymer membranes useful in accordance with the
present invention can include a variety of both hydrophilic and
hydrophobic polymers or copolymers. These polymers and copolymers
can include polyolefins, such as polyethylene and polypropylene,
ethylene-vinyl acetate, polyvinyl acetate, polyether block amides,
polyurethane, polyamides, such as nylon, cellulose and cellulose
derivatives, polyvinyl chloride, polyvinyl alcohol, polystyrene,
polymethyl methacrylate, polysilane, and polysiloxane. Among the
preferred membranes for use in the present invention are included
ethylene-vinyl acetate, polyethylene, such as CoTran 9711 of 3M
Corporation, and SULOPOR of DSM Corporation, or ultra-high
molecular weight polyethylene membrane.
[0044] Other examples of the polymer membranes which can be used
in accordance with this invention include copolyester membranes,
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preferably between 0.5 and 3.0 mils in thickness, with MVTRs
between about 1,000 and 15,000 g/m2/24 hrs.; polyurethane membranes
which are from about 0.5 to 3.0 mils in thickness with MVTR values
between about 1,000 and 10,000 g/m2/24 hrs.; polyether block amides
with MVTRs between about 2,000 and 10,000 g/m2/24 hrs.; 9% ethylene
vinyl acetate polymer membranes which are between about 1 and
mils in thickness; and hydrophilic polyethylene membranes which
are between about 1.0 and 10.0 mils in thickness.
[0045] The various pharmaceutically active agents which can be
used in accordance with the present invention are legion. Indeed,
essentially any active agent which has been or could be applied
transdermally is a candidate for the present invention. With any
such active agent, or drug, or class thereof, the present invention
can be utilized to manipulate the natural rate of transdermal or
transmucosal delivery, and/or to insert a greater amount of the
active agent into a dosage form thereof. Manipulation of the
natural rate of delivery could, for example, be in connection with
certain steroids. That is, endogenous steroid levels, such as with
estrogens, progestens and androgens, follow circadian patterns.
The present invention could then be employed to obtain a "spike"
shortly after application. Other active agents, such as analgesics
can sometimes work fast by delivering a bolus in order to terminate
pain, followed by a steady but slower rate of delivery to prevent
return of the pain.
[00461 On the other hand, insertion of greater amounts of active
agent into a dosage form could be applied, for example, in
connection with active agents such as testosterone. This drug can
be suspended in an acrylic adhesive in order to delivery a
therapeutic dose, but the testosterone can crystallize within the
matrix in an unpredictable manner. By application of the present
invention, delivery of the drug can be accomplished with sufficient
drug loaded into the system, and there would be no driving force
for crystallization of the testosterone, unless the solvent being
utilized were lost from the membrane during storage. In another
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example, attempts to load a sufficient amount of fentanyl into a
polyisobutylene adhesive matrix in a patch in order to deliver a
therapeutic dose thereof over three days will result in the
adhesive matrix having lost its adhesive properties. By utilizing
the present invention, however, the fentanyl will remain dissolved
throughout the adhesive matrix and that matrix can still remain
tacky
[0047] As for the active agents themselves, again as noted
above, there is essentially no limit on the potential use of any
such active agents which can be delivered transdermally or
transmucosally.
[0048] Suitable systemic drugs include, without limitation,
anti-microbial agents such as penicillin, tetracycline,
oxytetracycline, chlortetracycline, chloramphenicol, and
sulfonamides; sedatives and hypnotics such as pentabarbital sodium,
phenobarbital, secobarbital sodium, codeine,
(a-bromoisovaleryl)urea, carbromal, and sodium phenobarbital;
psychis energizers such as a 30(2-aminopropyl) indole acetate and
3-(2-aminobutyl) indole acetate; tranquilizers such as reserpine,
chlorpromazine hydrochloride, and thiopropazate hydrochloride;
hormones such as adrenocorticosteroids, for example, 6a-
methylprednisolone; androgenic steroids, for example,
methyltestosterone, and fluoxymesterone; estrogenic steroids, for
example estrone, 17(3-estradiol and ethinyl estradiol; progesterone,
and norethindrone; and thyroxide; antipyretics such as aspirin,
salicylamide, and sodium salicylate; morphine and other narcotic
analgesics; anti-diabetics, e.g., insulin; cardiovascular agents,
e.g. nitroglycerin, and cardiac glycosides such as digitoxin,
digoxin, ouabain; anti-spasmodics such as atropine, methscopolamine
bromide, methscopolamine bromide with phenobarbital; anti-malarials
such as the 4-aminoquinolines, 9-amino-quinolines, and
pyrimethamine; and nutritional agents such as vitamins, essential
amino acids, and essential fats.
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[0049] The backing layer which is impermeable to the drug, and
the adhesive primarily has as its objectives to prevent seepage of
the active agent or adhesive through the backing layer. If, for
example, the backing layer is coated on the surface in contact with
the remainder of the device with an adhesive layer that is active
agent impermeable, this impermeable adhesive layer will essentially
perform this purpose even if the backing layer is not totally
impermeable to the active agent. Thus, it is not necessary in all
instances that the backing layer be impermeable to the active
agent, although in most instances it normally is, and when it is
not a layer providing this barrier function, such as an active-
ingredient-impermeable adhesive layer, it will be situated between
the backing layer and the remainder of the device such as the
membrane.
[0050] The backing layer may also be impermeable to the solvent
or other fluid medium contained within the transdermal system.
However, in some embodiments it is possible that the backing layer
might be permeable to the solvent or other fluid component therein.
For example, a portion of this liquid medium might be permitted to
evaporate through the backing layer. This could thus provide a
cooling effect, or it could act as a secondary method for
attenuating the "spike" of active agent through the skin or mucosa
of the patient by allowing a portion of the solvent or the enhancer
to escape from the system other than by passing through the skin or
mucosa of the patient.
[0051] The actual material used for the outer surface of the
backing layer will depend on the properties of the materials in
contact therewith. Some suitable materials include, for example,
cellophane, cellulose acetate, ethyl cellulose, plasticized vinyl
acetate-vinyl chloride copolymers, ethylene-vinyl acetate
copolymer, polyethylene terephthalate, nylon, polyethylene,
polypropylene, polyvinylidine chloride (e.g., SARAN), paper, cloth
and aluminum foil. The material used is preferably impermeable to
the active gent. The material which forms this backing layer may
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be flexible or non-flexible. Preferably, a flexible backing layer is
employed to conform to the shape of the body to which the device is
attached.
[0052] Preferably, the material which forms the backing layer, such as
layer 12, is a film or a composite film. The composite can be a
metallized (e.g., aluminized) film or a laminate of two or more films
or a combination thereof. For example, a laminate of polyethylene
terephthalate and polyethylene or a polyethylene/metallized
polyethylene terephthalate/polyethylene laminate can be employed. The
preferred polymers include polyethylene, polypropylene, polyvinyl
chloride, polyesters such a polyethylene terephthalate (MYLAR') , and
polyvinylidine chloride (SARAN) . More particularly, a highly preferred
composition of the present invention employs highly occlusive layers of
polyethylene terephthalates or polyvinylidine chloride as a backing
layer.
[0053] The transdermal patch systems of the present invention also
include a release or releasable layer for temporarily covering the
adhesive surface prior to application. The release layer can be made of
the same material suitable for use in the backing layer as discussed
above. Such materials are preferably made releasable from the adhesive
layer by, for example, conventional treatment with silicone, TEFLON,
or other suitable coating on the surface thereof . The removal of the
device from the release layer may also be provided by mechanical
treatment of the release layer, such as by embossing same.
[0054] The release layer can also comprise various layers including
paper or paper-containing layers or laminates; various thermoplastics,
such as extruded polyolefins, such as polyethylene; various polyester
films, foil liners, other such layers, including fabric layers, coated
or laminated to various polymers, as well as extruded polyethylene,
polyethylene terephthalate, various polyamides, and the like, with the
polyester films being preferred. The release layer can also comprise
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vacuum metallized films such as metallized polyester or polypropylene
formed by vacuum deposition of aluminum for W and oxygen resistance.
[0055] Another possible release layer of the present invention includes
a laminate of an outer foil layer and an inner layer of plastic, such
as polyethylene or the like, which is rendered releasable not only by
means of a siliconized coating, but which also includes an embossed or
roughened surface. Embossment of the surface can be accomplished by a
number of conventional methods. In general, preparation of embossed
surfacing can be accomplished by the use of male-female tooling,
preferably enhanced by the application of heat. The principal intention
of this embossment process is to roughen the surface or render it
uneven so that less than the entire surface will be in physical contact
with the corresponding adhesive layer.
[0056] The preferred release layers of the present invention include
polyester films, preferably including a siliconized or fluorocarbon
coating thereon, such as SCOTCH" PAK 1022 from 3M Corporation.
[0057] As is also discussed above, the fluid medium which is
incorporated into the membranes of the present invention can include
water, C1-C3 alcohols, dimethyl sulfoxide, N,N-dimethylacetamide,
polyethylene glycol, polysorbitols, polyethylene oxide,
polyoxyethylene, dimethicone, mineral oil/paraffin, vegetable oils, and
the like.
[0058] In accordance with the present invention, the solvent to be
incorporated into the membrane is preferably an alcohol. Alcohols in
accordance with the present invention can include monoalcohols, such as
methanol, ethanol, propanol, isopropanol, butanol, and tertbutyl alcohol.
The alcohol may also be a generally low molecular weight diol, triol, or
polyol, i.e., glycols such as propylene glycol, triols such as glycerol,
and polyalkylene glycol having an average molecular weight of less than
about 400. For example, the solvent may be polyethylene glycol having an
average molecular weight of between about 200 and about
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400. The solvent in accordance with the present invention can thus
comprise a normal short chain polyol of between about 2 and about 4
carbons in length. Such polyols may include 1,4 butanediol,
glycerol, ethylene glycol, propylene glycol, and the like. Also
useful in accordance with the present invention are acetates such
as, for example, ethyl acetate, cellulose acetate, vinyl acetate
and the like.
[0059] It is also possible to use additional components in the
transdermal systems of the present invention, such as dyes,
permeation enhancers, cross-linkers, adhesion promoters, gelling
agents, crystallization inhibitors, anti-inflammatory agents, and
the like.
[0060] Penetration enhancers can also be included as the fluid
media of the present invention. These penetration enhancers are
intended to promote penetration of the active agent through the
skin, and suitable enhancers include those described in U.S. Patent
No. 5,503,844, including monovalent, saturated and unsaturated
aliphatic and cycloaliphatic alcohols having 6 to 12 carbon atoms
such as cyclohexanol, lauryl alcohol, and the like; aliphatic and
cycloaliphatic hydrocarbons such as mineral oil; cycloaliphatic and
aromatic aldehydes and ketones such as cyclohexanone; N,N-di(lower
alkyl)acetamides such as N,N-diethyl acetamide and N,N-dimethyl
acetamide, N,N-dimethyl acetamide, N-(2-hydroxyethyl)acetamide and
the like; aliphatic and cycloaliphatic esters such as isopropyl
myristate and lauricidin; N,N-di(lower alkyl) sulfoxides such as
decylmethyl sulfoxide; essential oils, nitrated aliphatics,
aliphatic and cycloaliphatic hydrocarbons such as N-methyl-2-
pyrrolidone and azone; salicylates, polyalkylene glycol silicates;
aliphatic acids such as oleic acid and lauric acid, terpines such
as cineole, surfactants such as sodium lauryl sulfate, siloxanes
such as hexamethyl siloxane; mixtures of the above materials; and
the like.
[0061] Examples of fluid carriers that may be combined with the
active agent in the membrane layer include simple alcohols,
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polyethylene glycols, polypropylene glycols, polyester and
polyether polyols, epoxidized linseed oils and simple liquid esters
such as triethyl citrate, dicyclohexyl phthalate, diisoacyl
adipate, fatty acids (oleic, lauric and the like), salts of fatty
acids, fatty alcohols, fatty esters (CERAPHYLS and the like),
terpenes and like. The preferred fluid carriers include
short-chain alcohols, fatty acids, fatty esters, fatty alcohols,
polyethylene glycols and polypropylene glycols.
[0062] Examples of binders that can be combined with the active
agent in the adhesive and/or membrane layers of the present
invention include conventional hydrogels formed using water-soluble
or water-insoluble gums or resins, with or without known cross-
linking agents. The gums or resins include agarose, alginates,
alkyl and hydroxyalkyl celluloses, such as hydroxyethyl cellulose
and hydroxypropyl cellulose, amylopectin, arabinogalactin,
carboxymethyl cellulose, carrageenan, eucheuma, ucoidan,
furcellaran, gelatin, guar gum, gum agar, gum arabic, gum ghatti,
gum karaya, gum tragacanth, pypenia, keratin laminaran, locust bean
gum, pectin, polyacrylamide, poly(acrylic)acid and homologs,
polyethylene glycol, poly(ethylene oxide), poly(hydroxyalkyl)
methacrylate, polyvinyl alcohol, polyvinylpyrrolidone, propylene
glycol alginate, starch and modified analogs, tamarind gum, N-vinyl
lactam polysaccharides and xanthan gum. In addition, such
hydrogels can be formed by the copolymerization and cross-linking
of both hydrophilic and hydrophobic monomers, such as hydroxy-alkyl
esters of acrylic acid and methacrylamide, n-vinyl-l-pyrrolidone,
alkyl acrylates and methacrylates, vinyl acetate, acrylonitrile and
styrene. Other binders suitable for use with the present invention
include veegum, higher molecular weight polyglycols, and the like.
[0063] The binders that are preferred for use with the present
invention include cellulose esters, polyvinyl pyrrolidones and
polyacrylates. Binders in accordance with the present invention
can be prepared as a liquid, paste, semi-solid or solid that is
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combined with the active agent and incorporated into the membrane
layer.
(0064] A therapeutic adhesive formulation for use in accordance
with the present invention includes various adhesive formulations
which can be used as part of the transdermal drug delivery systems
hereof. Preferably, these adhesive formulations are monolithic
structures and preferably include both an adhesive formulation and
a pharmaceutically active agent therein. The adhesive formulations
which can be used in accordance with the present invention include
many such formulations known in the art. Broadly these include
acrylics, silicones, polyisoalkalines, rubbers, vinyl acetates,
polyisobutylene rubber, polybutyldiene, styrene-butadiene(or
isoprene)-styrene block copolymer rubber, acrylic rubber, and
natural rubber; vinyl-based high molecular weight materials such as
polyvinyl alkyl ether, polyvinyl acetate, a partially saponified
product of polyvinyl acetate, polyvinyl alcohol and polyvinyl
pyrrolidone; cellulose derivatives such as methyl cellulose,
carboxylmethyl cellulose and hydroxypropyl cellulose;
polysaccharides such as pullulan, dextrin and agar; polyurethane
elastomers; and polyester elastomers. Of course, the adhesives
must be biocompatible and nonirritating. They must also allow for
a patch to adhere firmly to the skin or mucosa of a patient in need
of treatment by a patch, but not be so adhesive so as to injure the
patient as the patch is removed. It is also important that the
adhesive be selected such that it is compatible with the other
components of the therapeutic adhesive formulation of the present
invention. It has been found that, as a group, the acrylic
adhesives are particularly useful and compatible in this regard and
therefore, it is preferred that the adhesive used be acrylic based.
More specifically, acrylic adhesives in accordance with the present
invention may preferably be (meth)acrylic acid such as butyl
(meth)acrylate, pentyl (meth)acrylate, hexyl (meth)acrylate, heptyl
(meth)acrylate, octyl (meth)acrylate, nonyl (meth)acrylate, decyl
(meth)acrylate, undecyl (meth)acrylate, dodecyl (meth)acrylate, and
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tridecyl (meth)acrylate, and copolymers of at least one of the
above esters and other monomers copolymerizable therewith.
[0065] Examples of the preferred polyacrylate adhesives for use
in the transdermal system of the present invention are those sold
under the trademark DuroTak 87-2194, 87-2620, 87-2052, 87-2852,
87-2054, 87-2979 and 87-6173 by National Starch and Chemical
Corporation. Other suitable adhesives are sold under the trademark
GELVA-Multipolymer Solution, GELVA 2873 and 2883 by Surface
Specialties, Inc.; and silicone adhesives sold under the trademark
BIO-PSA 7-4300 and 7-4500 by Dow Corning Corporation. Other
preferred adhesives include polyisobutylene and styrene-butadiene
rubber adhesives.
[0066] Examples of the copolymerizable monomer include carboxyl
group-containing monomers such as (meth)acrylic acid, itaconic
acid, crotonic acid, maleic acid, maleic anhydride and fumaric
acid; sulfoxyl group-containing monomers such as styrenesulfonic
acid, arylsulfonic acid, sulfopropyl acrylate,
(meth) acryloyloxynaphthalenesulfonic acid,
acrylamidomethylpropanesulfonic acid and acryloyloxybenzenesulfonic
acid; hydroxyl group-containing monomers such as hydroxyethyl
(meth)acrylate and hydroxypropyl (meth)acrylate; amide group-
containing acrylic monomers such as (meth)acrylamide,
dimethyl(meth)acrylamide, N-butylacrylamide,
tetramethylbutylacrylamide and N-methylol(meth)acrylamide;
alkylaminoalkyl group-containing acrylic monomers such as
aminoethyl (meth)acrylate, dimethylaminoethyl (meth)acrylate,
diethylaminoethyl (meth)acrylate and tertbutyl (meth)acrylate;
alkyl esters of acrylic acid containing an ether bond in the
molecule thereof such as methoxyethyl (meth)acrylate, ethoxyethyl
(meth)acrylate, butoxyethyl (meth)acrylate, tetrahydrofurfuryl
(meth) acrylate, methoxyethylene glycol (meth)acrylate,
methoxydiethylene glycol (meth)acrylate, methoxypolyethylene glycol
(meth)acrylate and methoxypolypropylene glycol (meth)acrylate;
vinyl monomers such as N-(meth)acryloylamino acid; functional
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monomers such as urethane, urea or isocyanate ester of acrylic
acid; and vinyl monomers such as (meth)acrylonitrile, vinyl
acetate, vinyl propionate, vinyl pyrrolidone, vinyl pyridine, vinyl
pyrazine, vinyl piperadine, vinyl piperidone, vinyl pyrimidine,
vinyl pyrrole, vinyl imidazole, vinyl caprolactam, vinyl oxazole,
vinyl thiazole, vinyl morpholine, styrene, a-methylstyrene and
bis(N,N'-dimethylaminoethyl) maleate.
[0067] The above alkyl esters of (meth)acrylic acid and
copolymerizable monomers include isomers in which the alkyl portion
is straight or branched, and isomers and derivatives in which the
position of substituents is different.
[0068] It is desirable from a standpoint of the balance between
adhesive properties to the skin and cohesion that the ratio of the
alkyl ester of (meth)acrylic acid to the copolymerizable monomer in
the acrylic pressure-sensitive adhesive material is 50:50 to 99:1
by weight. When alkyl esters of (meth)acrylic acid containing an
ether bond in the molecule thereof are used from the standpoint of
the low skin irritating properties, it is desirable that the ratio
of the alkyl ester of (meth)acrylic acid/the alkyl ester of
(meth)acrylic and containing an ether bond in the molecule/the
other copolymerizable monomer is 40 to 80/59 to 10/1 to 40.
[0069] It is preferred that the adhesive formulations be
subjected to suitable chemical cross-linking treatment (e.g.,
copolymerization of cross-linkable monomers and addition of a
cross-linking agent) or physical cross-linking treatment (e.g.,
irradiation with ultraviolet rays and ionizing radiations such as
electron beam).
[0070] In accordance with the present invention, the amount of
adhesive generally utilized ranges from between about 30 to about
99 percent by weight based on the weight of the resulting
formulation (excluding backing and release films). Preferably, the
amount of adhesive used ranges from between about 65 to about 95
percent by weight based on the total weight of the formulation
(excluding backing and release films).
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[0071] Acrylic polymeric adhesives in accordance with this
aspect of the present invention include between about 40% and about
90% of a C4-C12 alkyl acrylate as the principal monomeric component.
Any alkyl acrylate having between 4 and 12 carbons which.has been
used for the formulation of transdermal adhesives can be used,
although, of course, other acrylates are also contemplated.
Traditional C4-C12 alkyl acrylates useful in accordance with the
present invention include, for example, 2-ethylhexyl acrylate,
butyl acrylate, n-decyl, n-nonyl, 2 ethyoctyl, isooctyl and
dodecyl-acrylate Generally, the C4-C12 alkyl acrylate in accordance
with the present invention will be used in a matter of between
about 40 and about 90% based on the weight of the finished adhesive
material. More preferably,. however, the amount of the C4-C12 alkyl
acrylate will range from between about 60% to about 80% by weight,
based on the weight of the adhesive.
[0072] The properties of the acrylic polymeric adhesive can be
dramatically altered depending upon whether or not a hardening
monomer is used and the type of hardening monomer used. It has
been found that the use of between about 10% and about 40% by
weight of a C1-C4 alkyl acrylate hardening monomer, in combination
with the C4-C12 alkyl acrylate, can provide an acrylic polymeric
adhesive system capable of providing desirable therapeutic
delivery, as well as structural integrity. Examples of C1-C4 alkyl
acrylate hardening monomers useful in accordance with the present
invention include methyl acrylate, methyl methacrylate,
ethylacrylate, ethyl methacrylate, hydroxyethyl acrylate and
hydroxy propyl methacrylate. More preferably, the amount of C1-C4
alkyl acrylate hardening monomer useful in accordance with the
present invention ranges from between about 15% to about 30% based
on the weight of the adhesive.
[0073] In accordance with the present invention, it is also
desirable to use a functionalizing monomer which facilitates cross-
linking. Functionalizing monomers provide functional groups for
cross-linking. Such functionalizing monomers are well known in the
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art and include, for example, acrylic acid, hydroxy ethylacrylate,
methacrylic acid, and acrylamide . It should be noted, however, that
when using an acrylate hardening monomer in an acid form, it is
preferred to use a functionalizing monomer, such as acrylic acid,
whereas, where the hardening monomer is an alcohol, compounds such as
hydroxy methylacrylate should be chosen. Functionalizing monomers are
generally provided in the range of about 1% to about 20%.
[0074] It is also desirable to include a cross-linking agent.
Cross-linking agents can include butyl titanate, polybutyl titanate,
aluminum zinc acetate and other multivalent metals, methylol ureas and
melamines Generally the cross-linking agent is provided in an amount of
between about 0.005 and about 2% the adhesive .
[0075] Cross-linking can be effected in many ways depending upon a
number of factors. Most importantly, cross-linking depends upon the
mode of action of the cross-linking agent. Most of the acrylic
polymeric adhesive formulations commercially available use cross-
linking agents which will be activated upon the drying of the
formulation. It is not the heat which activates these agents but rather
the removal of the solvent by, for example, evaporation or drying.
Drying to remove these solvents can by done under completely
conventional conditions such as 100 to 140 F. It should be noted that
certain formulations are commercially available without cross-linkers.
For example, GELVATM 1430 is identical to GELVATM 1753 except that it
does not include a cross-linker. This allows one to accommodate
situations where no cross-linking is needed (such as when very low
concentrations of drug are used) or to custom select a cross-linker
that has a different mode of action.
[0076] The present invention can also be appreciated with reference to
the following examples.
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Example 1
[0077] An active estradiol blend was made by sonicating
estradiol hemihydrate and 200 proof ethyl alcohol in a 4-ounce
glass jar. Polyvinyl pyrrolidone, fumed silica, propylene glycol
and DuroTak 87-2194 adhesive were added and the blend was mixed
using an air driven mixing blade. The active blend was coated
knife over a roll as the skin contact layer at 18 mil wet on
Medirelease 2226, then dried at 54 C for 5 minutes and 85 C for
8 minutes. The anchor layer was placebo polyisobutylene coated at
8 mil wet on Medirelease 2226, dried at 54 C for 5 minutes and 85 C
for 8 minutes, then laminated to 0.5 mil PET. The release liner
was peeled off the polyisobutylene anchor layer. A piece of
CoTran 9711, the same size as the anchor adhesive, was placed on
the exposed anchor adhesive. The anchor layer with the CoTran 9711
was soaked in a bath of 200 proof ethyl alcohol for 2 minutes. The
anchor layer was removed from the bath. The active skin contact
layer was then laminated on top of the exposed membrane impregnated
with ethyl alcohol. Patches were die cut and pouched in Barex
pouching. The patch exhibited a delivery "spike" in vitro.
Example 2
[0078] An active adhesive blend was made by sonicating estradiol
hemihydrate and ethanol until the estradiol hemihydrate was
dispersed (approx. 3 min.). Polyvinyl pyrrolidone was added to the
premix and dissolved. Next, propylene glycol was added and
swirled. Finally, DuroTak 87-2194 adhesive and fumed silica were
added. The blend was mixed in a glass jar with an air driven
mixing blade, after which the blend was rolled on a jar roller
overnight to degas. An active adhesive blend was coated knife over
roll twice on Medirelease 2226. An anchor layer was coated at
8 mil wet, and the skin contact layer was coated at 19 mil wet.
Both layers were dried at 41 C for 4 minutes and 77 C for
4 minutes. To make the finished patch, the anchor layer was
laminated to Mediflex 1000. The release liner was peeled off the
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anchor layer. A 9o ethylene vinyl acetate membrane (2.0 mil) was
saturated with 200 proof ethyl alcohol by submerging the membrane
in an ethyl alcohol bath. The saturated membrane was removed from
the bath and placed on the adhesive side of the anchor layer. The
skin contact layer (adhesive side) was laminated on top of the
exposed membrane with ethanol. This formulation exhibits a
delivery "spike" in vitro.
Example 3
[0079] An active blend was made by sonicating the estradiol
hemihydrate (0.41 g) in 200 proof ethyl alcohol (3.09 g) for
3 minutes. The polyvinyl pyrrolidone (1.04 g) was dissolved in the
premix and sonicated for 3 minutes. Propylene glycol (4.80 g),
DuroTak 87-2194 (60.79 G) and fumed silica (0.17 g) were added to
the premix. The entire blend was mixed with an air driven mixing
blade for 3 minutes, after which a glass jar was rolled on the jar
roller overnight to degas. The laminates were coated knife over
roll at 14 mil wet on Medirelease02249 to obtain a coat weight of
55.0 g/m2. the laminate was dried at 41 C for 4 minutes and 77 C
for 4 minutes. The first laminate was laminated to Mediflex 1500
backing as the anchor layer. The release liner was peeled off the
anchor layer. A piece of DSM Solupor 10P05A membrane was submerged
in a bath of 200 proof ethyl alcohol for at least 1 minute. The
membrane was removed form the bath and wiped with a lint-free wipe
to remove excess ethyl alcohol. After 1 minute in ambient air, the
wet membrane was placed on the exposed adhesive of the anchor
layer. The second laminate (skin contact layer) was immediately
laminated on top of the exposed membrane loaded with ethyl alcohol.
Appropriate size patches were immediately die cut from the laminate
and sealed in polyethylene pouching material. This formulation
exhibits a delivery "spike" in vitro.
Example 4
[0080] An active blend was made by sonicating albuterol sulfate
in ethyl acetate for 5 minutes in a 4-ounce glass jar. Mineral
oil, lauryl alcohol, and lauric acid were added to the premix.
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Polyisobutylene adhesive was added to the jar and the blend was
mixed with an air driven mixing blade for 3 minutes, after which
the blend was rolled on the jar roller to degas. The blend was
coated twice on Medirelease 2226 at 10 mil wet, and dried at 55 C
for 5 minutes and 85 C for 8 minutes. One laminate was laminated
to the Mediflex 1000 backing, the release liner was peeled off and
7 cm2 pieces of CoTran 9711 were placed on the exposed adhesive.
Fifty pL of 1-Octanol was pipeted onto each piece of CoTran 9711.
The other laminate was laminated on top of the CoTran 9711
impregnated with 1-Octanol and 10 cm2 patches were die cut. The
patches were pouched immediately. The in vitro flux lag time was
shortened compared to control without a membrane impregnated with
1-Octonal.
Example 5
[0081] An active blend was made by sonicating albuterol sulfate
in ethyl acetate for 3 minutes in a 4-ounce glass jar. Mineral oil
and lauric acid were added to the premix. Polyisobutylene adhesive
was added to the jar and the blend was mixed with an air-driven
mixing blade for 3 minutes, after which the blend was rolled on the
jar roller to degas. The blend was coated twice on
Medirelease 2226 at 50 g/m2, and dried at 55 C for 5 minutes and
85 C for 8 minutes. One laminate was laminated to the
Mediflex 1000 backing, the release liner was peeled off and 10 cm2
pieces of CoTran 9711 impregnated with lauryl alcohol were placed
on the exposed adhesive. The second laminate was laminated on top
of the CoTran 9711 impregnated with lauryl alcohol and 10 cm2
patches were die cut.
[0082] Although the invention herein has been described with
reference to particular embodiments, it is to be understood that
these embodiments are merely illustrative of the principles and
applications of the present invention. It is therefore to be
understood that numerous modifications may be made to the
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illustrative embodiments and that other arrangements may be devised
without departing from the spirit and scope of the present
invention as defined by the appended claims.
INDUSTRIAL APPLICABILITY
[00831 The invention relates to the transdermal administration
of various pharmaceutical compounds, and most particularly to the
control of the amount and rate of drug administration to the
patient in need thereof.
27
